Project Summary Alzheimer's disease (AD) is a devastating neurodegenerative disorder that is clinically characterized by progressive impairment of memory and cognitive functions. Many lines of genetic and biochemical evidence strongly highlight a central role of the amyloid pathway in the pathogenesis of AD where abnormal accumulation of amyloid beta (A?) into extracellular toxic plaques is responsible for the neurodegeneration and resulting dementia in AD. Our active R01 grant (R01 NR015674) is focused on developing a non-invasive magnetic nanoparticle (MNP) hyperthermia platform to eradicate biofilm infections in which a remotely applied high-frequency alternating magnetic field (AMF) is used to rapidly heat MNPs that are bound to bacterial biofilm matrix and pathogens. During the course of the R01 project, we have successfully established and optimized the MNP hyperthermia platform and this application is to take advantage of the new technology with an aim to target and eradicate A?. Our immediate goal for this application is to demonstrate the feasibility of applying our targeted MNP hyperthermia technology as a promising therapeutic to treat AD by means of targeting and removing toxic A? deposits in a minimally invasive manner. We hypothesize that a targeted and localized heating of MNPs bound to A? plaques is sufficient to disrupt the hydrophobic interactions and hydrogen bonds between fibrils, which may result in better treatment efficacy by clearing A? plaques. To prove our hypothesis, we propose to (1) characterize the effect of MNP/AMF on mediating a targeted disruption of A? plaques, (2) examine the effect of MNP/AMF-mediated disaggregation of A? plaques on microglia-mediated clearance of A? disaggregates, and (3) develop a strategy to deliver MNPs through the brain endothelial cells using a focused ultrasound-mediated opening of blood-brain barrier (BBB). The biomedical safety of the MNP hyperthermia treatment has been validated in the clinical application of the technology in treating brain tumors in human. Our innovation lies in the integration of our well-established MNP hyperthermia technology into FDA- approved focused ultrasound and amyloid-targeting antibody that is surface-engineered on MNPs to meet a series of challenges in current therapies of AD. Our proposed application focuses on the treatment of AD and is within the scope of the current active R01 in that we directly utilize the experimental knowledge and technology as a new treatment option for AD. The successful completion of the proposed study will allow us to apply the same strategy to develop a potential therapeutic for the treatment of AD.